PROJECT SUMMARY The DIAN-TU was formed to design and manage interventional therapeutic trials and find a treatment that provides cognitive benefit for those certain to develop autosomal dominant AD (ADAD). The DIAN-TU trial platform is now fully operational in 6 countries, 24 sites, 3 languages and nearing completion of enrollment in October 2015 for the first two drugs. Initial funding for the DIAN-TU trial platform established the infrastructure and operations for executing clinical trials in ADAD and acknowledged the need for evolution within this platform. The DIAN-TU Next Generation Prevention Trial will add two new drug arms to the DIAN-TU trial platform and propose key design changes that allow the platform to test next generation drugs with diverse mechanisms of action more quickly. Significant innovations include: (1) cognitive run-in period prior to drug administration to provide greater power to detect drug effects, (2) self-administered cognitive testing, (3) pre- defined dose escalation algorithm to safely maximize target engagement, (4) four year cognitive endpoint adaptive trial design that includes both early biomarker and later cognitive interims to inform early efficacy or futility, (5) novel imaging (e.g. Tau PET and diffusion basis spectrum imaging MRI) and cerebrospinal fluid measures (6) ADAD Disease Progression Model to detect changes in cognition earlier and with fewer participants compared to Mixed-Effect Model Repeated Measure. Taken together, this innovative approach for testing disease modifying therapies has the potential to definitively test the amyloid hypothesis and accelerate identification of effective drugs for the prevention and treatment of AD. Many disease modifying therapies currently in development target A?, which is believed to be the initiator and earliest change in the AD process. These A? therapies may be most beneficial in the ADAD population and earlier in the disease to delay the onset of dementia. A fundamental and unresolved question is which target will provide the best cognitive response. The trial design is a multi-center, double blind, randomized, placebo-controlled, four year cognitive endpoint registration study of two potential disease modifying therapies in 230 individuals at risk for and with dominantly inherited Alzheimer's disease. The study will test the ability of a BACEi and an anti-oligomeric A? antibody to slow or prevent cognitive decline in asymptomatic (CDR 0, >70%) or mildly symptomatic (CDR 0.5 or 1, <30%) ADAD mutation carriers in the range of -15 to +10 years with respect to estimated age of cognitive symptom onset. 115 subjects per drug program will receive either drug or placebo with 3:1 randomization for four years to determine clinical benefit of the primary outcome of DIAN-TU cognitive composite and secondary outcomes of cognitive and clinical measures, safety, and AD biomarkers.